Monoheterocyclic compounds



United MON OHETEROCYCLIC COMPOUNDS porafion of New Jersey No Drawing. Application February 28, 1957 Serial No. 642,959

10 Claims. (Cl. 260-306.7)

This invention relates to certain 2-imino-thiazolidine-4- ones of the formula:

S NO-Om in which R, and R stand for hydrocarbon radicals containing more than 2 carbon atoms, salts of such compounds, as well as the process for their preparation.

The hydrocarbon radicals R and R are more especial- 1y alkyl radicals containing from 3 to 14 carbon atoms, e. g. propyl, isopropyl, butyl, isobutyl, pentyl, or especially isopentyl, and furthermore S-methylpentyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl radicals; or alkenyl radicals, e. g. allyl or methallyl radicals.

Salts of the new compounds of this invention are particularly therapeutically useful acid addition salts such as those with inorganic acids, such as, hydrohalic acids, e. g. hydrochloric, hydrobromic or hydriodic acid; perchloric, nitric or thiocyanic acid; or sulfuric or phosphoric acids; or those with organic acids, such as, formic, acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, ascorbic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, p-aminobenzoic, p-hydroxybenzoic, anthranilic, cinnamic, mandelic, salicylic, p-aminosalicylic, Z-phenoxybenzoic, 2-acetoxy-benzoic, methane sulfonic, ethane sulfonic, hy-

droxyethane sulfonic, benzene sulfonic, p-toluene sulfonic, naphthalene sulfonic or sulfanilic acid or methionine, tryptophane, lysine or arginine.

The new Z-imino-thiazolidine-4-ones and the salts thereof of this invention inhibit the growth of microorganisms such as bacteria or fungi and may be used as medicaments in the treatment of infections caused by microorganisms. Thus, the 2-imino-thiazolidine-4-ones of the formula:

JI'QOR' in which R stands for hydrocarbon, e. g. alkyl or alkenyl radicals containing from 3 to 6 carbon atoms, and the therapeutically useful salts thereof, are particularly active against various type of Mycobacteria, such as Mycobizcterium tuberculosis or Mycobacterium leprae and can be used as antitubercular or antileprotic agents. An outstanding representative of this group of compounds is, for example, the Z-imino-thiazolidine-4-one of the formula:

SVN@0 cmomomona. OLIL I atent O "ice and the therapeutically useful acid addition salts, e. g. a hydrohalide thereof.

2-imino-thiazolidine-4-ones of the formula:

formula:

STNQO CH2 GCHI Q QHmw,

and the therapeutically useful acid addition salts, e. g. a hydrohalide thereof.

The new compounds may be used as medicaments in the form of pharmaceutical preparations, which contain the new compounds or salts thereof in admixture with .a pharmaceutical organic or inorganic solid or liquid carrier suitable for enteral, parenteral or topical administration. For making up the preparations there can be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly, cholesterol or any other known carrier for medicaments. The pharmaceutical preparations may be, for example, in the form of tablets, salves, dragees, creams, or in liquid form as solutions, suspensions or emulsions. If desired, they may contain auxiliary substances, such as preserving agents, stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They may also contain, in combination, other therapeutically useful substances.

The new 2-imino-thiazolidine-4-ones and their salts are prepared by reacting an N,N-d.i-substituted thiourea of the formula:

in which R and R stand for hydrocarbon radicals containing more than 2 carbon atoms, with an acetic acid or an ester thereof, substituted in a-position by a reactive esterified hydroxyl group and, if desired, converting any resulting salt into the free base, and/ or converting a free base obtained into a salt thereof.

A reactive esterifie'cl hydroxyl group is more especially a hydroxyl group esterified with a strong mineral acid, particularly a hydrohalic acid, e. g. hydrochloric, hydrobromic or hydriodic acid; or with a strong organic acid, e. g. p-toluene sulfonic acid. An acetic acid ester is more especially an acetic acid lower alkyl ester, e. g. methyl, ethyl or propyl ester.

-The startingmaterials used in this reaction-are known or may be prepared according to methods known for the preparation of analogous compounds. Thus, N,N'-disubstituted thioureas may be prepared by reacting substituted isothiocyanate with a substituted aniline; for example, the 4-isopentoxyphenyl-isothiocyanate may be reacted with 4-isopentoxyaaniline to form the N,N-di-(4- isopentoxyphenyl)-thiourea. Or, carbon disulfide may be reacted with-the .appropriately substitutedaniline derivative in the presence of a catalytic amount of an alkali metal salt of an alkyl xanthate, according to C. F. Huebner et al., I. Am. Chem..Soc., vol. 75, p. .2274 (1953), to yield a symmetrically N,N-bis-substituted thiourea.

The described reaction is carried out in the presence or absence of a solvent, at room 'or at an elevated temperature, in an open or closed. vessel under pressure, or in .the presence of an inertgas such as nitrogen; 'It is preferably conducted inasolvent, for example, an alcohol, suchras ethanol, if :desired,.in-the presence of an alkali metal salt of a lower alkanoic acid, e. g. sodium acetate; an :aromatic hydrocarbon, 'suchaas benzene; a halogenated' hydrocarbon, xsuch astchloroform; or a lower carboxylic'acid in the presence ,of an alkali metal salt of such an acid, for example, glacial acetic acid in the presence of sodium acetate. If desired, the-reaction may be completed more rapidlyiby refluxing the'mixture for 2 to 8 hours. Any unreacted .thiourea 'whichcontaminates the final product, may be identified by infrared studies or by the formation of an insoluble black precipitate upon addition of lead acetate to an alcoholic solution of the product. If necessary, the reaction may be1completed by reacting the product containing any unreacted thiourea with an additional amount of the u-halogeno-acid or an ester thereof.

Depending on the conditions used the new compounds are obtained in the form'of the-free bases or salts thereof. The salts may be converted into the free bases in the customary way, e. g. by reaction with an alkali metal hydroxide, such as sodium hydroxide. The free bases may be'transformed into their therapeutically useful acid addition salts by reaction with appropriate inorganic or organic acids, e. g. the acidsoutlined above.

The following examples are intended to illustrate the invention. They are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example I A mixture of 13.8 g. of l,3-bis-(4'-propoxyphenyl)- thiourea, 5.8 g. of chloroacetic acid, and 11.0 g. of anhydrous fusedsodium acetate is suspended in 150 ml. of anhydrous ethanol and refluxed for 3%, .hours. The reaction mixture is filtered hot and allowed to crystallize under refrigeration. The material thus obtained is dissolved in benzene at room temperature, and the unreacted thiourea is filtered off. After removal of the solvent the filtrate yields the 2-(4'-propoxyphenylimino)- 3-(-4'-propoxyphenyl)-thiazolidine-4-one of the formula:

s Tar-Q CHaHv OLN Q-Ormnn which is twice recrystallized from a mixture of benzene and petroleum ether, M. P. 9698 C.

The hydrochloride may be prepared by adding to an ethanolic solution of 2-(4'-propoxyphenyl-imino)-3-(4'- propoxyphenyl)-thiazolidine-4-one a solution of hydrogen chloride in a mixture of ethanol and ether. The oxalate may be prepared by adding oxalic acid to the ethanolic solution of 2-(4-propoxyphenyl-imino)-3-(4-propoxyphenyl)-thiazolidine-4-one.

Example 2 A mixture of 34 g. of 1,3-'bis (p -*allyloxyphenyl)- thiourea, 14.5 g. of chloroacetic acid and 25 g. of anhydrous sodium acetate is suspended in absolute ethanol and refluxed for 3 hours. The solution is filtered hot, the ethanol removed and the solid extracted with hot benzene. The solvent is removed from this extract and the residue is recrystallized twice from a mixture of benzene and methanol. The 2-(4'-allyloxyphenyl-imino) 3 (4'- allyloxyphenyl)-thiazolidine-4-one of the formula:

SVNQO CHzOH=CHs is recrystallized twice from cold benzene, M. P. 76- 7 6.5 C.

Example 3 melts at l32-133.

Example 4 A mixture of 19 g. of 1,3-bis-[4'-(3-methylpentoxy)- phenyH-thiourea, 4.8 g. of chloroacetic acid and 12.5 g. of anhydrous sodium acetate in ml. isopropanol is refluxed for 4 /2 hours. The solution is filtered hot and the filtrate allowed to crystallize in the cold. The 2- [4'-(3-methylpentoxy)-phenyl-imino] 3 [4-(3-methylpentoxy)-phenyl]-thiazolidine-4-one of the formula:

I BVN0 omcmcnomom l l -0 Gunmen-0112011;

is dissolved in hot cyclohexane, filtered free of a small amount of insoluble matter and allowed to crystallize; M. P. 109-111".

Example 5 A mixture of 30 g. of 1,3-bis-(4'-heptoxyphenyl)- thiourea, 6.2 g. of chloroacetic acid and 12 g. of anhydrous sodium acetate in 200 ml. isopropanol is refluxed for 6 hours. The solution is filtered hot and the crystals obtained by chilling the solution are recrystallized three times from isopropanol. The 2-(4-heptoxyphenylimino) 3-(4'-heptoxyphenyl) thiazolidine-4-one of the formula:

melts at 97.5-98.5

Example 6 A mixture of 13.5 g. of 1,3-bis-(p-butoxyphenyl)-thiourea, 5.3 g. of chloroacetic acid and 9.9 g. of anhydrous sodium acetate in 150 ml. of anhydrous alcohol is refluxed for 3% hours. The solution is filtered hot and the alcoholic filtrate concentrated to a small volume. The solid thus obtained is recrystallized once from a mixture of chloroform and petroleum ether and twice from cyclohexane, yielding the 2-(4-butoxyphenylimino)3 (4'-butoxyphenyl) thiazolidine-4 one of the formula:

STN 0(CHs)aCH O=LN (C 2)aC s M. P. 103-106.

Example 7 A mixture of 13.9 g. of 1,3-bis-(p-isobutoxyphenyl)- thiourea, 5.3 g. of chloroacetic acid and 10.1 g. of anhydrous sodium acetate in 175 ml. of anhydrous alcohol is refluxed for 6 hours. The solid which separates out upon chilling overnight is filtered oif and washed with alcohol. A second crop, obtained by concentration of the filtrate and washings, is combined with the first, and the material obtained is recrystallized once from a mixture of chloroform and petroleum ether, once from a mixture of benzene and petroleum ether and once from cyclohexane. The 2-(4-isobutoxyphenyl-imino)-3-(4'- isobutoxyphenyl)-thiazolidine-4-one of the formula:

s No ornament), 0L1,

\QO cmcmom),

melts at 142-145".

What is claimed is:

1. A member of the group consisting of Z-imino-thiazolidine-4-ones of the formula:

in which R and R stand for hydrocarbon radicals containing 3 to 14 carbon atoms selected from the group consisting of alkyl and alkenyl radicals, and salts thereof.

2. 2-imino-thiazolidine-4-ones of the formula:

- isopentoxyisobutoxyin which R stands for an alkyl radical containing 7 to 14 carbon atoms.

10. 2-(4'-n heptoxyphenyl phenyl) -thiazolidine-4-one.

imino) -3-(4'-n heptoxy- References Cited in the file of this patent Bhargava: Chem. Abstracts, vol. 46, column 497 (1952).

Bhargava: Chem. Abstracts, vol. 46, column 11182 (1952). 

1. A MEMBER OF THE GROUP CONSISTING OF 2-IMINO-THIAZOLIDINE-4-ONES OF THE FORMULA: 